Peripheral neuropathy, commonly associated with diabetes, chemotherapy, and HIV- induced nerve damage, leads to progressive sensory deficits and nerve dysfunction. While muscarinic acetylcholine type 1 receptor (M1R) antagonism promotes sensory axon repair, the mechanisms underlying its neuroprotective effects remained unclear. Transient receptor potential melastatin-3 (TRPM3), a heat-sensitive cation channel, plays a crucial role in calcium signaling, mitochondrial function and neuronal metabolism, positioning it as a potential mediator of M1R antagonist-driven neuroprotection. This thesis investigated the mechanistic link between M1R antagonism and TRPM3 activation and explored the therapeutic potential of TRPM3 modulation in sensory axon regeneration. M1R antagonists pirenzepine (PZ) and muscarinic toxin 7 (MT7) enhanced TRPM3-mediated Ca²⁺ influx in dorsal root ganglion (DRG) neurons, an effect that was abolished by TRPM3 inhibitors or extracellular Ca²⁺ removal. TRPM3 activation using CIM0216 and pregnenolone sulfate (PS) elevated intracellular Ca2+, promoted AMP-activated protein kinase (AMPK) phosphorylation via the Ca²⁺/calmodulin-dependent protein kinase kinase  (CaMKKβ) pathway, leading to enhanced mitochondrial function, glycolysis, and tricarboxylic acid (TCA) cycle activity. Further analysis established that M1R antagonism stimulated TRPM3 by inhibiting phosphatidylinositol 4,5-bisphosphate (PIP2) hydrolysis, facilitating sustained calcium signaling and metabolic enhancement. TRPM3 knockdown via adeno-associated virus (AAV)-mediated shRNA suppressed the neurite-promoting effects of M1R antagonists, confirming its essential role in axonal plasticity. To assess whether these findings translated to an in vivo setting, the streptozotocin (STZ)-induced diabetic neuropathy model was utilized, which recapitulated key sensory impairments such as mechanical allodynia, slowed motor nerve conduction velocity (MNCV), and thermal hypoalgesia. PZ treatment restored sensory function in diabetic mice, but co-administration of TRPM3 inhibitors (isosakuranetin and primidone) abolished these improvements, confirming that M1R-mediated neuroprotection was TRPM3-dependent. Despite the emergence of sensory impairments at 16 weeks post-STZ induction, corneal nerve loss was less pronounced than expected, suggesting a gradual progression of neuropathy, where functional impairments preceded structural degeneration. However, TRPM3 inhibition significantly reduced corneal nerve density, further highlighting its potential role in sensory fiber maintenance. This thesis established TRPM3 as a key modulator of sensory axon regeneration via Ca²⁺-dependent AMPK signaling, demonstrating its potential as a therapeutic target for peripheral neuropathy and neurodegenerative disorders.